Composition for the treatment of ear infections and method

ABSTRACT

A composition for treating ear infections in animals includes an antifungal agent, an antibiotic agent, a steroidal anti-inflammatory agent, and an acid dissolved to form a liquid. The acid aids in keeping the steroidal anti-inflammatory agent in solution, and enhances the bactericidal effect of the composition. The method of preparing such composition includes dissolving the antifungal agent, steroidal anti-inflammatory agent, and acid in dehydrated alcohol, dissolving the antibiotic agent in propylene glycol, combining the two solutions together, heating the combination and then cooling the composition. Several drops of the composition are applied at least twice per day to the affected area of the animal&#39;s ear.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to compositions for thetreatment of ear infections in animals, and more particularly, to animproved composition of such type, as well as a method for manufacturingsuch improved composition.

2. Description of the Related Art

Ear infections, including bacterial infections such as otitismedia/externa, fungal infections, and yeast infections, are common amonganimals, especially canines. Various compositions for treating earinfections in animals are available on the market. One such prior artcomposition includes ketoconazole, ofloxacin, and triamcinolonediacetate, as active ingredients, along with dehydrated alcohol andpropylene glycol as solvents. However, this composition has a cloudyconsistency, and requires vigorous shaking prior to use. Among thedrawbacks of using such a non-homogeneous solution are the need torepeatedly shake such composition, and the lack of consistency inapplied dosage of such composition with each use.

Other compositions for treating ear infections in animals are knownwherein acetic acid is included as a mild antibacterial agent. However,those skilled in the art have been discouraged from attempting tocombine acetic acid with commonly-used steroidal anti-inflammatoryagents (such as triamcinolone diacetate, betamethesone, hydrocortisone,and dexamethasone) because acetic acid tends to drive these steroidalagents out of solution when ordinary methods of preparing suchcompositions are employed.

Accordingly, it is an object of the present invention to provide animproved composition effective for treating a variety of ear infectionsin animals, including bacterial infections, fungal infections, and yeastinfections.

Another object of the present invention is to provide such a compositionwherein the components thereof are more reliably maintained in solution.

Yet another object of the present invention is to provide such acomposition which need not be shaken so vigorously before each use.

A further object of the present invention is to provide such acomposition which can be administered in more consistent dosages.

A still further object of the present invention is to provide such acomposition which enhances the bactericidal effect of the steroidalanti-inflammatory agent by maintaining such agent in solution.

These and other objects of the present invention will become moreapparent to those skilled in the art as the description of the presentinvention proceeds.

SUMMARY OF THE INVENTION

Briefly described, and in accordance with the preferred embodimentsthereof, the present invention relates to a liquid composition which iseffective in the topical treatment of animal ear infections, its methodof formulation, and its manner of use to treat ear infections inanimals. The composition includes an antifungal agent, an antibioticagent, a steroidal anti-inflammatory agent, and an acid. In thepreferred embodiment, the composition further includes dehydratedalcohol and propylene glycol to dissolve and combine thepreviously-mentioned components.

The antifungal agent of the composition is preferably selected from thegroup of topical antifungal agents consisting of polyenes, azoles,allylamines, morpholines, antimetabolites, and combinations thereof.More specifically, the antifungal agent is ideally selected from thegroup of antifungal agents consisting of amphotericin, nystatin,fluconazole, itraconazole, clotrimazole, ketoconazole, terbinafine,5-fluorocytosine, and combinations thereof. The antifungal agent ispreferably provided in a concentration of approximately 5 to 50 gramsper liter of the composition.

The antibiotic agent used to formulate the aforementioned composition ispreferably selected from the group consisting of ofloxacin,ciprofloxacin, neomycin, polymixin B, enrofloxacin, marbofloxacin,orbofloxacin, and combinations thereof. Ideally, the antibiotic agent isprovided in a concentration of approximately 0.5 to 5 grams per liter ofthe composition.

The steroidal anti-inflammatory agent used to formulate theabove-described composition is preferably selected from the groupconsisting of triamcinolone, betamethesone, hydrocortisone,dexamethasone, and combinations thereof. In the preferred embodiment,the steroidal anti-inflammatory agent is provided in a concentration ofapproximately 0.25 to 2.5 grams per liter of the composition.

The acid used in formulating the aforementioned composition ispreferably selected from the group of acids consisting of citric acid,ascorbic acid, glycolic acid, tartaric acid, and combinations thereof.Ideally, this acid is an anhydrous acid to avoid the addition of waterto the composition. In the preferred embodiment of the presentinvention, the anhydrous acid is provided in a concentration of at leastapproximately 3 grams per liter of the composition.

A preferred form of such composition includes ketoconazole as theantifungal agent, ofloxacin as the antibiotic agent, triamcinolonediacetate as the steroidal anti-inflammatory agent, and citric acid.

Formulation methods are practiced to ensure that the resultingcomposition is homogeneous. In this regard, the preferred formulationmethod dissolves the antifungal agent, the steroidal anti-inflammatoryagent, and the anhydrous acid in liquid dehydrated alcohol to form afirst solution. The antibiotic agent is separately dissolved in liquidpropylene glycol to form a second solution. The first and secondsolutions are then combined to form a third solution; this thirdsolution is then heated. Ideally, the container used to heat the thirdsolution is covered, as by an impervious plastic film, and the thirdsolution is preferably stirred during heating. It is theorized that thestep of covering the container during prevents the dehydrated alcoholfrom evaporating and helps keep the steroidal anti-inflammatory agent insolution for a more homogenous solution. The solution is then cooledback to room temperature, preferably with continued stirring during thecool down phase.

The present invention also relates to the method of treating earinfections in animals by formulating a composition of the type describedabove, and applying such composition inside the ear of the animal atleast twice per day until the ear infection has been cured.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

A composition for the topical treatment of ear infections in animals,formulated in accordance with the preferred embodiment of the presentinvention, includes each of the following active ingredients: anantifungal agent, an antibiotic agent, a steroidal anti-inflammatoryagent, and an anhydrous acid. The preferred composition also includesdehydrated alcohol and propylene glycol as solvents for maintaining theforgoing active ingredients in solution.

An antifungal agent is generally defined as a drug that selectivelyeliminates fungal pathogens from a host with minimal toxicity to thehost. Some antifungal agents are selective in the types of fungalinfections which they attack, while other antifungal agents areeffective to treat a broad spectrum of fungal infections. Thecomposition of the present invention preferably utilizes a topicalantifungal agent of the latter type, having the ability to topicallytreat fungal infections caused by organisms such as Malassezia, Candida,Trichophyton, and Microsporum. Among the major groups of antifungalagents having applicability to the present invention are the polyenes,the azoles, the allylamines, the morpholines, and antimetabolites, aswell as combination of one or more of such antifungal agents. Whilebroad spectrum antifungal agents are preferred, the inventors furthercontemplate that selective antifungal agents may also be used, ifdesired.

The following are representative antifungal agents within each of thegeneral groups of antifungal agents mentioned above: (a) Polyenes:amphotericin and nystatin; (b) Azoles: fluconazole, itraconazole,clotrimazole, and ketoconazole: (c) Allylamines: terbinafine; and (d)Antimetabolites: 5-fluorocytosine. As mentioned above, combinations ofsuch antifungal agents may also be used, if desired. Other suitableantifungal agents which may be used in practicing the present inventionmay be found in “Drug Facts and Comparisons, 2002,” published by FactsAnd Comparisons.

When preparing the composition, the antifungal agent is preferablyprovided in powder form and is dissolved in dehydrated alcohol.Pre-formed tablets of such antifungal agent may be crushed to obtainsuch powder form. However, it is preferable to begin with an antifungalagent in pure powdered form, since fillers present in some tablets mayresult in a cloudy, non-homogeneous solution. The concentration of theantifungal agent used in preparation of the composition may rangebetween approximately 5 and 50 grams per liter, and more preferably,approximately 20 grams per liter.

An antibiotic or antibacterial agent is generally defined as a drug thatselectively eliminates bacteria from a host with minimal toxicity to thehost. As with the antifungal agent, the antibiotic agent is preferably abroad spectrum type antibiotic effective in killing a wide range ofbacteria; if desired, a selective-type antibiotic may also be used.Suitable antibiotic agents include, but are not limited to, ofloxacin,ciprofloxacin, neomycin, polymixin B, enrofloxacin, marbofloxacin,orbofloxacin, as well as combinations of such agents. Other suitableantibiotic agents which may be used in practicing the present inventionmay be found in “Drug Facts and Comparisons, 2002,” published by FactsAnd Comparisons.

It is again preferred that the antibiotic agent be provided in powderedform at the time that the composition is formulated. The antibioticagent powder is dissolved in liquid propylene glycol. Pre-formed tabletsof such antibiotic agent may be crushed to obtain such powder form.However, it is again preferable to begin with an antibiotic agent inpure powdered form, since fillers present in some tablets may not fullydissolve. The concentration of the antibiotic agent used in preparationof the composition may range between approximately 0.5 and 5 grams perliter, and more preferably, approximately 3 grams per liter.

Suitable steroidal anti-inflammatory agents, also known asadrenocortical steroids, for use with the composition of the presentinvention include triamcinolone, betamethesone, hydrocortisone,dexamethasone, and combinations thereof. Other suitable steroidalanti-inflammatory agents which may be used in practicing the presentinvention may be found in “Drug Facts and Comparisons, 2002,” publishedby Facts And Comparisons.

When preparing the composition, as in the case of the antifungal agentmentioned above, the steroidal anti-inflammatory agent is preferablyprovided in powder form and is dissolved in dehydrated alcohol. Onceagain, pre-formed tablets of such steroidal anti-inflammatory agent maybe crushed to form a powder, but it is preferable to begin with asteroidal anti-inflammatory agent in pure powdered form. Theconcentration of the steroidal anti-inflammatory agent used inpreparation of the composition may range between approximately 0.25 and2.5 grams per liter, and more preferably, approximately 1 gram perliter.

An anhydrous organic acid, or anhydride, is generally defined as awater-free molecule that has a pH lower than 7.0. Various anhydrousorganic acids which can be used in formulating the composition of thepresent invention include the anhydrous forms of citric acid, ascorbicacid, glycolic acid, and tartaric acid (and combinations thereof) all ofwhich may be dissolved in dehydrated alcohol. When preparing acomposition in accordance with the present invention, the anhydrousorganic acid is preferably provided in powdered form and is dissolved indehydrated alcohol. The concentration of acid used in preparation of thecomposition should be approximately at least 3 grams per liter ofcomposition, and more preferably, approximately 5 grams per liter ofcomposition.

The presence of the organic anhydrous acid in the composition of thepresent invention is believed to provide a beneficial, unexpected effectof increasing the antibacterial effectiveness of the compound.Additionally, it has been found that inclusion of the anhydrous acidalso helps to keep the steroidal anti-inflammatory agent fully-dissolvedin solution, whereas hydrous acids, such as acetic acid, tend to exhibitthe opposite effect. Accordingly, the composition of the presentinvention need not be agitated or shaken to a significant extent, if atall, after packaging, and dispensed dosages tend to be more uniform.

As noted above, the solvent used to dissolve the antifungal agent,steroidal anti-inflammatory agent, and anhydrous acid, is preferably aliquid dehydrated alcohol, e.g., dehydrated ethanol. It is preferable touse a minimal amount of such dehydrated alcohol, i.e., just enough todissolve the antifungal agent, steroidal anti-inflammatory agent, andanhydrous acid.

The solvent used for dissolving the antibiotic powder is preferablyliquid propylene glycol. In preparing the solution, a sufficient amountof propylene glycol is added to bring the solution to the desired finalconcentration.

After combining the dehydrated alcohol solution (containing thedissolved antifungal agent, steroidal anti-inflammatory agent, andanhydrous acid) and the propylene glycol solution (containing thedissolved antibiotic agent), the composition is continuously stirred andheated, generally at least until the solution becomes clear andhomogenous. The solution is then cooled to room temperature, whilecontinuously stirring. An impervious plastic film (similar to commonfood wrapping plastic film) or other seal is used to cover the open endof the container used to hold the solution during the heating andcooling processes, and the solution is preferably kept sealed or coveredthereafter, for a longer shelf life. It is believed that use of a seal,especially during the heating process, prevents the dehydrated alcoholfrom evaporating, and results in a homogenous mixture which does nothave to be stirred or shaken-up prior to use. Also, it is best toprepare the composition in a low-humidity environment to avoid theintroduction of water into the composition during formulation.

The following are examples of the method of preparing preparation acomposition in accordance with the present invention.

EXAMPLE 1

Step 1) Approximately 20 grams of the antifungal agent ketoconazolepowder (also known by the brand name “Nizoral®” available from JanssenPharmaceutica Products, LP of Titusville, N.J.), 1 gram of the steroidalanti-inflammatory agent triamcinolone diacetate powder (also known bythe brand name Aristocort®), and 5 grams of citric acid powder aredissolved in approximately 50 ml. of dehydrated liquid ethanol alcoholto form a first solution. All of such components are commerciallyavailable from Spectrum Pharmacy Products, 7400 N. Oracle Road, Suite228, Tucson, Ariz. 85704. While triamcinolone diacetate is a preferredsteroidal anti-inflammatory, triamcinolone acetonide may also be used.Those skilled in the art will recognize that triamcinolone acetonide isanother salt form of triamcinolone.

Step 2) Approximately 3 grams of the antibiotic agent ofloxacin powder(also known by the brand names “Floxin” and “Ocuflox”), available fromthe R. W. Johnson Pharmaceutical Research Institute of Raritan, N.J., isdissolved in approximately 100 ml. of propylene glycol liquid to form asecond solution.

Step 3) The first and second solutions formed in Steps 1 and 2,respectively, are combined within the container of a heating/agitationunit to form a third solution, and propylene glycol liquid is added tobring the total third solution volume to 1 liter. For example, aheating/agitation unit of the type known as the “Thermolyne CimarecIII™” brand hot plate, available from Barnstead Thermolyne Corp.International of Dubuque, Iowa, may be used for such purpose. This typeof hot plate includes a magnetic stirrer inside the solution container.The Thermolyne Cimarec III™ brand hot plate is adjusted to a heatsetting of “7”, and to an agitation setting of “5.” The solutioncontainer is also covered with the impervious plastic film prior toheating, preferably, as soon as all the components are added thereto.

Step 4) The solution of step 3 is heated, while being continuouslystirred, until it turns from a cloudy yellow to a clear reddish purplecolor, at which point the source of heat is turned off. At this point,the solution may appear to be steaming. This heating process takes alittle over two hours; during such heating process, the solution changescolor from yellow to orange, from orange to red, and finally to areddish purple color at the end of approximately two hours.

Step 5) The solution is left on the hot plate and allowed to cool toroom temperature while continuing to be stirred during the cool-downphase. Cooling time is approximately three hours.

EXAMPLE 2

The same procedure is followed as set forth in Example 1 above, exceptthat 3 grams of the antibiotic agent ciprofloxacin is used instead ofthe ofloxacin mentioned in Example 1 above. Ciprofloxacin is availablefrom Bayer Corporation Pharmaceutical Division, of West Haven, Conn.

The compositions formed in the above examples result in non-cloudy,homogeneous solutions, which do not have to be stirred, or shaken-up,prior to use. Dosage and period of use of the composition may vary fromapproximately 1 to 10 or more drops (note: 1 cm³ of compositioncorresponds to approximately 20 drops) in each ear, at least once, andpreferably, twice daily, for several days to several weeks, depending onthe severity of the infection. The preferred dosages are approximately 3to 4 drops, twice daily, for smaller dogs; 6 to 7 drops, twice daily,for medium-sized dogs; and 9 to 10 drops, twice daily, for large dogs.If desired, the infected ear may be cleansed or flushed prior toadministration of the composition.

The composition of Example 1 was used on dogs having ear infections ofvarying degrees of severity, and was administered into the affectedear(s) according to the following tapering dose schedule: ½ dropperfuldoses of such composition twice daily for the first week; ½ dropperfuldoses once daily for the second week; then ½ dropperful doses everyother day for a total of four more doses. In dogs having particularlysevere infections, infected ears were first flushed with ear flushescontaining 2% acetic/2% boric acid before treating with the compositionof Example 1. The above protocol was repeated as necessary when symptomsof ear infection reoccurred. Use of the composition proved to be verysuccessful, especially for dogs having chronic, recurring earinfections. It was found that the duration between bouts of earinfections increased due to use of the present composition, and that theneed for the use of oral antibiotics to manage chronic ear infectionsbecame less frequent.

In one test, the composition of Example 1 was used to treat a dog thathad a history of chronic ear problems over approximately the previoussix years. Throughout such six-year time period, several treatments,including various antibiotics and ear medications, had been used, totreat such ear infection. While such treatments all seemed to work for aperiod of time, none of such treatments was successful in completelyeliminating the infection. However, when the composition of Example 1above was administered, at a dosage of about 1 to 2 drops, in each ear,twice a day, for 10 days, a noticeable improvement of the symptoms,including the dog's hearing, could be seen by 3-4 days into thetreatment; at the end of such treatment, the dog's ear infection hadcompletely cleared up.

In another case, an animal practitioner provided animal owners with thecomposition of Example 1 for use in treating animals who suffered fromprolonged chronic ear infections. The animal practitioner instructed theanimal owners to administer the drops at a dosage of 4-5 drops in eachear, twice daily, for a period of time ranging from 7 days to 6 weeks,depending upon the severity of the infections. The owners were furtherinstructed to first clean each infected ear with a commerciallyavailable ear cleansing product called OtiCalm™, manufactured by DVMPharmaceuticals of Miami, Fla., prior to each administration of thepresent composition, and then to administer drops of the presentcomposition into the infected ears and massage the drops into the ear,and allow the drops to remain in the infected ear. After examining thetreated animals, it was found that use of the composition resulted in100% success rate in significantly reducing the inflammatory processobserved in the ear canals and appropriately controlling infection,although known medications used in the past on such animals had failed.Additionally, no adverse effects were noted.

Those skilled in the art will now appreciate that an improvedcomposition has been described that effectively treats a variety of earinfections in animals, including bacterial infections, fungalinfections, and yeast infections. When formulated as described above,the active ingredients are more reliably maintained in solution,allowing the composition to be administered in more consistent dosageswithout the need to be shaken vigorously before each use, and withimproved antibacterial effect.

While the present invention has been described with respect to preferredembodiments thereof, such description is for illustrative purposes only,and is not to be construed as limiting the scope of the invention.Various modifications and changes may be made to the describedembodiments by those skilled in the art without departing from the truespirit and scope of the invention as defined by the appended claims.

1. A method of preparing a composition for the treatment of earinfections in animals, said method comprising the steps of: a. combiningthe following components in a container, the container having an openend: i. an antifungal agent; ii. a steroidal anti-inflammatory agent;iii. an anhydrous organic acid; iv. liquid dehydrated alcohol; v. anantibiotic agent; and vi. liquid propylene glycol; b. covering the openend of the container after step a. and before step c.; c. heating thecontents of the container while the container is covered; and d.following step c, cooling the heated contents of the container while thecontainer is covered.
 2. The method of claim 1 wherein the step ofcovering the open end of the container includes the step of applying animpervious plastic film over the open end of the container prior to saidheating step.
 3. The method of claim 1 further comprising the step ofstirring the contents of the container during said step of heating thecontents of the container.
 4. The method of claim 3 further comprisingthe step of stirring the contents of the container during said step ofcooling the contents of the container.
 5. The method of claim 1 whereinsaid heating step is performed until the contents of the container haschanged from an initial cloudy yellow color to a clear reddish purplecolor.